Acheiving instantaneous control of G-protein coupled receptors using light as a ligand

使用光作为配体实现 G 蛋白偶联受体的瞬时控制

• 批准号: G0801731/1
• 负责人: Robert Lucas
• 金额: $ 49.69万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0801731%2F1
• 关键词: Acheiving; instantaneous; control; protein; coupled

The discovery and development of drugs that can influence human behaviour and physiology has played a crucial role in the huge advances in medicine that have occurred over the last century. However, future progress is likely to depend in large part upon our ability to overcome some of the inherent limitations in this pharmaceutical method for treating disease. A well known problem with using drugs is that of side effects, which occur because drugs commonly have effects on multiple parts of the body. Many otherwise effective drugs are lost because of the need to minimise such adverse effects. An additional problem with drugs is that, in comparison with the natural changes in our physiology that they hope to regulate, their effects build up rather slowly and can hang around for a long time. This contributes to our tendency to become desensitised to drugs and also stops them being used in conditions in which we would like more immediate and reversible effects. For these reasons, there is a pressing need to develop new ways of adjusting our physiology that go beyond the achievements of pharmacy. We propose developing such a technology. Our approach will be to modify a group of proteins called GPCRs to make them light sensitive. GPCRs appear in practically every cell of our body. Their job is to fine tune the cell?s activity and physiology according to signals released from neighbouring cells and other parts of the body. Because they are so influential they have long been recognised as a good way of treating the symptoms of disease. Indeed more than half of currently prescribed drugs are designed to alter their activity. By making GPCRs photosensitive, we will be able to use light rather than drugs to tweak their activity. Unlike drugs, light can be switched on and off very rapidly. Light can also be applied at high doses to a single group of cells without influencing the rest of the body. These features mean that we will be able to use the new GPCRs to achieve extremely fine tuned alterations in physiology way beyond what is currently possible using drugs. In the first instance we will use this technology in animal experiments that increase our knowledge of how common medical conditions (including obesity, depression and insomnia) come about. In time, it will become a completely new way of treating medical conditions.

可能影响人类行为和生理的药物的发现和开发在上个世纪发生的医学巨大进展中起着至关重要的作用。但是，未来的进步很大程度上取决于我们克服这种治疗疾病的药物中一些固有局限性的能力。使用药物的一个众所周知的问题是副作用，这是因为药物通常对人体多个部位具有影响。由于需要最大程度地减少这种不良反应，因此许多其他有效的药物被丢失了。药物的另一个问题是，与他们希望调节的生理学的自然变化相比，它们的作用相当缓慢，可以长期闲逛。这有助于我们倾向于对药物脱敏的趋势，并阻止它们在我们希望更直接和可逆的效果的条件下使用。由于这些原因，迫切需要开发新的方法来调整我们的生理学，这些方法超出了药房的成就。我们建议开发这种技术。我们的方法是修改一组称为GPCR的蛋白质，以使其对光敏。 GPCR几乎出现在我们身体的每个细胞中。他们的工作是根据来自相邻细胞和人体其他部位释放的信号来微调细胞的活性和生理。由于它们的影响力很大，他们长期以来一直被认为是治疗疾病症状的好方法。实际上，当前处方药的一半以上旨在改变其活动。通过使GPCR具有光敏性，我们将能够使用光而不是药物来调整其活动。与药物不同，可以很快打开和关闭光线。光也可以以高剂量将其应用于一组细胞，而不会影响身体的其余部分。这些功能意味着我们将能够使用新的GPCR来实现生理方法的极度微调改变，而不是当前使用药物的可能性。首先，我们将在动物实验中使用这项技术，以增加我们对常见医疗状况（包括肥胖，抑郁和失眠）的了解。随着时间的流逝，它将成为治疗医疗状况的全新方法。